Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/16—Amides, e.g. hydroxamic acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/13—Amines

Definitions

• the present invention relates to novel hydroxylamine derivatives each having an unsaturated hydrocarbyl group, production of these compounds and use of these compounds, namely, their use in anthelmintic processes.
• hydroxylamine derivatives each having an unsaturated hydrocarbyl group are known in the art, namely, N-propargyl-N-benzoyl-O-methylhydroxylamine in Moore et al: J. Medical Chemistry, Vol. 12, p.45 (1969); N-allyl-N-benzoyl-O-propylhydroxylamine in Johnson et al: J. Organic Chemistry, Vol. 36, p.284 (1971); O-methyl-N-allylhydroxylamine in French Patent No.2,122,338; and O,N-diallylhydroxylamine in Eur. Patent Application No. 29,171 (1981).
• hydroxylamine derivatives in accordance with the present invention are each represented by the formula A:
• Preferred combounds of formula A are those in which R is an alkyl having up to 5 carbon atoms. Examples of these compounds are as follows: and Other preferred compounds of formula A are those in which R o is hydrogen and which are each in the form of a salt with an acid. An example of these compounds is:
• the present invention relates to an anthelmintic method and to an anthelmintic composition wherein an anthelmintic activity of the compounds represented by the following formula A' is utilized.
• R o , R a and R b are the same as those defined in the formula A except for the following two points.
• Combinations of R o , R a and R b are selected from the group of (1), (2), (4) and (5) in the formula A, whereas the combinations are selected from the group of (1) through (5) inclusive in the formula A'.
• the group of (3) is:
• the compounds of the formula A' are of low toxicity to warm-blooded animals and have high anthelmintic - activity.
• the use of the compounds thus provides convenient and effective anthelmintic method and composition.
• the anthelmintic method comprises administering orally to an animal afflicted with a parasite a compound represented by the formula (A').
• the anthelmintic composition comprises a compound represented by the formula (A') and a carrier.
• the present invention in still another aspect thereof, provides methods of producing compounds represented by the formula (A').
• the methods depend on the type of the compound to be produced. Details of the methods will be given hereinlater.
• Hydroxylamine derivatives containing unsaturated hydrocarbyl groups of this invention can be divided into five main types of compounds (1-1 to 5).
• Compound (I-l) are N-propargyl-N-acylhydroxylamine derivatives as is represented by the following formula. [wherein R 1 and R a are the same as those presented in the combination (1) of R o , R a , and R b in the definition of the compounds of the formula (A).]
• examples of R 1 which constitutes an N-acyl group preferably include: (1) hydrogen, and linear or branched lower alkyl groups having about 1 to 5 carbon atoms such as methyl, ethyl, n-propyl, n-butyl, isobutyl, and n-pentyl; (2) linear or branched lower alkenyl groups having about 3 to 5 carbon atoms such as 2-propenyl, 2-butenyl, and isobutenyl; (3) middle alkyl or alkenyl groups having about 6 to 8 carbon atoms; (4) higher alkyl or alkenyl groups such as the alkyl chain of lauric acid (C 11 H 23 ), the alkyl chain of stearic acid (C 17 H 35 ), and the alkenyl chain of oleic acid (C 17 H 31 ); (5) phenyl groups; and (6) phenyl groups substituted by halogen atoms such as fluorine, chlorine, bromine,
• Preferable phenyl groups are those substituted by halogen atoms and lower alkyl groups.
• R a which is a constituent of formula (I-1), preferably include (1) linear or branched lower alkyl groups having about 1 to 5 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and pentyl and (2) linear or branched lower alkenyl groups having about 3 to 5 carbon atoms such as allyl, crotyl, methallyl, and 2-pentenyl.
• the compounds of formula (I-1) can be produced by an objectively appropriate method. Specifically, they can be produced by, for example, a method represented by the following equation (A)-l: [wherein R 1 and R a are the same as those defined in formula (I-1), and X stands for a halogen atom (particularly, chlorine, bromine or iodine)].
• reaction of the compounds of formula (II-1) with the compounds of formula (III-1) in accordance with equation (A-l) can be conducted by allowing the compounds of formula (III-I) of at least equal mol per mol of the compounds of formula (II-1) to react therewith in the presence of a deacidification agent.
• solvents which can be used include water, acetone, methanol, ethanol, and tetrahydrofuran.
• Preferable solvents are water, methanol, ethanol, and mixtures thereof.
• deacidification agents examples include sodium alkoxides such as sodium methoxide and sodium ethoxide, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, and alkali metal carbonates such as sodium hydroxide and potassium carbonate. These can be used singly or as mixtures thereof.
• the amount of the deacidification agent used in mols is at least equal to that of the compound of formula (III-1).
• the reaction is ordinarily conducted at a temperature of 0 - 100°C, preferably from room temperature to 50°C, with stirring for a period of from 1 hr to 3 days.
• the compounds produced by the above mentioned method can be easily isolated for purification by an ordinary separation method such as solvent extraction, distillation, recrystallization, and silica gel column chromatography.
• the compounds of formula (III-1) used as starting materials in the above mentioned equation (A) are well-known ones. Also, the compounds of formula (II-1) as starting materials can be produced on the basis of, for example, the known process (Journal of Organic Chemistry, Vol. 25, p. 1734, 1960).
• the compound (I-2) of this invention are N-alkenyl-N-acylhydroxylamine derivatives represented by the following formula: [wherein R 1 , R a and R 3 are the same as those defined in the combination (2) of R o , R a , and R b in the definition of the compounds of the formula (A).]
• R 1 and R a are the same as those enumerated for compounds (I-1).
• R 3 is hydrogen or a methyl group as set forth above.
• the compounds of formula (I-2) can be produced by an objectively appropriate method. Specifically, they can be produced by, for example, a method represented by the following equation (A-2): [ wherein R 1 , R a and R 3 are the same as those defined for formula (I-2), and X stands.for a halogen atom (particularly chlorine, bromine, or iodine)].
• reaction of the compounds of formula (II-2) with the compounds of formula (III-2) in accordance with equation (A-2) can be conducted by allowing the compounds of formula (III-2) of a quantity in mols at least equal to the quantity of the compound of formula (11-2) to react therewith in the presence of a deacidification agent in solvents.
• Compounds (I- 3 ) are N-alkenyl-N-acyl-0-alkenyl- hydroxylamine derivatives which are represented by the following formula, some of which are publicly known. [wherein R 1 is the same as that set forth in the definition of the compounds of formula (A), and R 2 and R 3 are hydrogen and a methyl group respectively.]
• reaction of the compounds of the formula (II-3) with the compounds of the formula (III-3) in accordance with the equation (A-3) in the presence of a deacidification agent in solvents can be conducted by allowing the compounds of formula (III-3) in a quantity in mols at least equal to that of the compound of formula (II-3) to react therewith.
• the compounds (1-4) of this invention are hydroxylamine derivatives or salts thereof which are represented by the following formula: [wherein R a and R b are the same as those defined in the combination (4) of R°, R a and R b in the definition of the compounds of the formula (A)].
• R a which is a constituent in the formula (I-4), are preferably: (1) linear or branched lower alkyl groups having about 2 to 5 carbon atoms such as ethyl, n-propyl, n-butyl, isobutyl and n-pentyl; (2) linear or branched lower alkenyl groups having about 3 to 5 carbon atoms such as allyl, crotyl methallyl, and 2-pentenyl; and (3) linear or branched lower alkynyl having about 3 to 5 carbon atoms such as propargyl and 2-butynyl.
• R b which is a constituent in the formula (1-4) are preferably (1) linear or branched lower alkenyl groups having about 3 to 5 carbon atoms such as allyl, crotyl, methallyl and 2-pentenyl, and (2) linear or branched lower alkynyl groups having about 3 to 5 carbon atoms such as propargyl and 2-butynyl.
• the salts of the compounds of formula (I-4) are also offered.
• the salts are those of inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, and those of organic acids such as acetic acid, propionic acid, oxalic acid, citric acid, tartaric acid, lactic acid, and p-toluenesulfonic acid.
• inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid
• organic acids such as acetic acid, propionic acid, oxalic acid, citric acid, tartaric acid, lactic acid, and p-toluenesulfonic acid.
• pharmacologically allowable salts are particularly suitable.
• the compounds of formula (I-4) can be produced by an objectively appropriate method. Specifically, they can be produced by, for example, a method represented by the following equation (A-4): [ wherein R 1 , R a and R are the same as those defined hereinbefore.]
• Hydrolyzing-reaction of the compounds of formula (II-4) in accordance with equation (A-4) can be conducted in the presence of acids in solvents.
• solvents which may be used are water, acetone, methanol, ethanol, and tetrahydrofuran.
• Preferable solvents are water, methanol, ethanol, and mixtures thereof.
• acids which may be used are inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, and organic acids such as acetic acid, trifluoroacetic acid, and p-toluenesulfonic acid.
• inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid
• organic acids such as acetic acid, trifluoroacetic acid, and p-toluenesulfonic acid.
• the reaction is ordinarily conducted at a temperature of 0 - 100°C, preferably from room temperature to 70°C, for a period of from 1 hr to one day with stirring.
• the compounds of formula (II-2) which can be used as a starting material in the equation (A-1) can be produced by the method for producing the compounds (I-1) and by the method for producing the compounds (I-5) which will be described later or by processes on the basis of these methods.
• the compound (I-5) of this invention are N,O-dipropargyl-N-acylhydroxylamine derivatives which are represented by the following formula: [wherein R is the same as that defined in the combination (5) of R o , R a and R b in the definition of the compounds of the formula (A).]
• R 1 are the same as those set forth with respect to compounds (I-1).
• the compounds of formula (1-5) can be synthesized in accordance with an objectively appropriate method with respect to forming or converting of each bond.
• This method A-5 is conducted in accordance with the following equation (A-5). [wherein R 1 is the same as that set forth above; R c is a lower alkyl group (particularly, one having about 1 to 5 carbon atoms); and Y designates a halogen atom (particularly, chlorine, bromine, and iodine).]
• Hydroxylamine source compounds i.e., hydroxylamine free bases or salts in an amount preferably of 1.0 to 1.2 mol per mol of the compounds represented by formula (II-5) in equation (A-5) are caused to react with the compounds of formula (II-5), and then the compounds of formula (III-5) of at least 2 mol per mol of the compounds of formula (II-5) are caused to react therewith to produce the compounds of formula (I-5) of this invention.
• reaction represented by .equation (A-5) be ordinarily carried out in solvents.
• solvents which can be used are such solvents that can be used commonly in the reaction of the compounds of formula (II-5) with hydroxylamine source compounds and in the reaction of the compounds of formula (II-5) with compounds of formula (III-5) at the later stage.
• Specific examples are water, acetone, methanol, ethanol, and tetrahydrofuran.
• Particularly preferable solvents are alcohols such as methanol and ethanol, and mixtures thereof.
• the net reaction at the first stage of equation (A-5) is the reaction of the compounds of formula (11-5) with hydroxylamines.
• the hydroxylamines can be in the form of salts with various kinds of acids as well as in the form of free bases.
• the compounds in both the forms are called hydroxylamines source compounds in this invention.
• acids which can form salts in this case are hydrochloric acid, phosphoric acid and other inorganic acids, and oxalic acid and other organic acids.
• alkalis in the condensation reaction of the compounds of formula (11-5) with hydroxylamines.
• the alkalis can be used not only for condensation reaction but also as a deacidification agent when a free base is prepared from hydroxylamine salts and also as a deacidification agent when the compounds of formula (III-5) at the later stage of the reaction are caused to react.
• the alkalis are alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, sodium alkoxides such as sodium methoxide and sodium ethoxide, alkali metal carbonates such as sodium carbonate and potassium carbonate.
• alkali metal hydroxides or alkali metal carbonates are ordinarily used with advantage.
• the alkalis to be used are desirably used in an amount of at least 3 mols in total per mol of the compounds of formula (II-5) in the case where there are intended to be generated from hydroxylamine salts free- bases thereof to continuously cause successive reaction of the compounds of formula (II-5).
• the first stage reaction of the compounds of formula (II-5) with hydroxylamine source compounds is ordinarily conducted at a temperature of about 0 - 50°C, preferably at room temperature, for a period of about 1 - 24 hours with stirring.
• the later stage reaction of the compounds of formula (II-5) with the compounds of formula (III-5) is ordinarily conducted at a temperature of about 0 - 100°C, preferably of from room temperature to 50°C, for a period of about from 1 hr to 3 days with stirring.
• the compounds of this invention can also be produced by a method represented by equation (B-5). [wherein R 1 and Y are as set forth above, and X stands for a hydrogen atom or alkali metals.]
• the reaction of the compounds of formula (IV-5) with the compounds (111-5) in accordance with equation (B-5) can be conducted by causing the compounds of formula (111-5) of at least 2 mols per mol of the compounds of formula (IV-5) to react therewith in the presence of a dioxidizer in a solvent.
• solvents which can be used are water, acetone, methanol, ethanol, and tetrahydrofuran.
• Preferable solvents are water, methanol, ethanol, and mixtures thereof.
• deacidification agents which can be used are sodium alkoxides, alkali metal hydroxides, and alkali metal carbonates.
• alkali metal hydroxides such as sodium hydroxide and potassium hydroxide or alkali metal carbonates such as sodium carbonate, and potassium carbonate or mixtures of the hydroxides and carbonates are preferably used.
• the amount of the deacidification agent to be used is required to be at least 2 mols per mol of the compounds of formula (IV-5) in the case where-the agent is used when X stands for a hydrogen atom in formula (IV-5). However, in the case where the deacidification agent is used when X-stands for an alkali metal atom in formula (IV-5), the amount of the agent to be used is required to be at least one mol per mol of the compounds of formula (IV-5).
• the reaction is ordinarily conducted at a temperature of about 0-100°C, preferably from room temperature to 50°C, for a period of from 1 hr to 3 days with stirring.
• reaction of the compounds of formula (V-5) with the comounds of formula (III-5) in accordance with equation (C-5) can be conducted by allowing the compounds of formula (III-5) in a quantity of at least one mol per . mol of the compounds of formula (V-5) to react therewith in the presence of a deacidification agent in solvents.
• solvents which can be used are water, acetone, methanol, ethanol, and tetrahydrofuran.
• Preferable solvents are water, methanol, ethanol and mixtures thereof.
• deacidification agents which can be used are sodium alkoxides such as sodium methoxide and sodium ethoxide, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, and alkali metal carbonates such as sodium carbonate and potassium carbonate. These deacidification agents may be used alone or as mixtures thereof.
• the amount of a deacidification agent used is at least one mol per mol of the compounds of formula (V-5).
• the reaction is ordinarily conducted at a temperature of 0 - 100°C, preferably from room temperature to 50°C, for a period of from 1 hr to 3 days with stirring.
• the compounds of formula (11-5) and the compounds of formula (III-5) which can be used as starting materials are known compounds.
• the compounds of formula (IV-5) which can be used as starting materials in equation (B-'5) are also known compounds.
• the compounds of formula (V-5) which can be used as starting materials in equation (C-5) can be produced by, for example, the known method of Moore et al [Journal of Medical Chemistry, Vol. 12, p.45 (1969)].
• Parasitosis is prevalent in domestic animals such as pig, horse, cattle, sheep, goat, dog, cat, etc. and poultry such as chicken and is economically a serious problem.
• the compounds of the formula (A') have very high anthelmintic activities against a wide scope of various parasites as enumerated above.
• Examples of the animals for which the compounds represented by the formula (A') are practically applicable are domestic animals such as pig, sheep, horse, cattle, goat, dog and cat and poultry such as chicken, turkey and duck. Furthermore, these compounds can be administered at any stage of growth of such animals, that is, when they are young, during growth, or after they are fully grown.
• the dosage of the compounds of the formula (A') to be administered depends on the compound actually employed and the body weight of the animal to which the compound is administered, but, in general, a dose of over 0.1 mg/Kg per day, preferably between 1 mg/kg and 100 mg/kg, is administered in order to achieve effective results,
• the compounds of the formula (I) can be administered directly without addition of other components, or alternatively they can be administered as mixtures with physiologically nontoxic solid carriers or liquid carriers. Further, it is also possible to administer the compounds of the formula (I) by adding them directly into the feed or drinking water for the animals, or by adding the above mixtures with suitable carriers directly to the animals or into their feed or drinking water.
• the solid carriers employed in this case are, for example, orally digestable vessels such as gelatin capsules, or crude wheat powder, corn starch, defatted rice bran, calcium carbonate, calcium phosphate, talc, kaolin, white earth, lactose, sucrose, gelatin, stearic acid, agar, pectin and analogues thereof and also may be any of various excipients conventionally used in pharmaceuticals.
• orally digestable vessels such as gelatin capsules, or crude wheat powder, corn starch, defatted rice bran, calcium carbonate, calcium phosphate, talc, kaolin, white earth, lactose, sucrose, gelatin, stearic acid, agar, pectin and analogues thereof and also may be any of various excipients conventionally used in pharmaceuticals.
• nontoxic liquids such as water, isotonic sodium chloride solution, paraffins (e.g., petroleum distillates), vegetable oils (e.g., peanut oil, soybean oil or sesame oil), alcohols, (e.g., ethyl alcohol or glycerol), and glycols (e.g., propylene glycol or polyethylene alcohol) can be employed.
• paraffins e.g., petroleum distillates
• vegetable oils e.g., peanut oil, soybean oil or sesame oil
• alcohols e.g., ethyl alcohol or glycerol
• glycols e.g., propylene glycol or polyethylene alcohol
• auxiliary agents or additives such as emulsifiers, dispersants, suspending aids, humectants, etc. can also be used, depending on the necessity.
• the compound in a form such as a tablet, capsule, pellet, giant pill, or powder.
• a liquid carrier in the form of a soft gelatin capsule or a suspension.
• the compound of the formula (A') when dissolved or dispersed in a liquid carrier, it can be administered parenterally to an animal by injecting subcutaneously, intramuscularly, intravenously or intraperitoneally.
• the compound of the present invention can be administered according to an aqueous recipe by the use of a vegetable oil such as peanut oil or soybean oil, or alternatively an aqueous parenteral recipe by the use of a watersoluble vehicle such as glycerol or polyethylene glycol can also be used.
• These recipes generally contain the compound of the formula (A') in an amount of 0.1 to 30% by weight.
• the reaction liquid was concentrated under reduced pressure and, after addition of water, was made acidic with concentrated hydrochloric acid to carry out extraction with chloroform. After the resulting chloroform layer was washed with a 10% aqueous sodium hydroxide solution, it was washed with water, dried with magnesium sulfate, concentrated and then distilled under reduced pressure to produce 5.5 g N ,O-dipropargyl-N-acetylhydroxylamine (Compound No.El) as a pale yellow oily substance.
• a liquid preparation was prepared by mixing with stirring 50 g of a compound of Compound No.Al, 49 g of ethanol and 1 g of polyvinyl alcohol. This liquid preparation was mixed under stirring into the drinking water for an animal to a concentration of 1% to be suspended in the drinking water, and the resultant suspension was administered to the subject animal.
• Compound No.A10 To 20 g of Compound No.A10 were added 1 g of sodium carboxymethyl cellulose, 0.2 g of sodium citrate and distilled warter for injection to prepare a mixture of a total quantity of 100 ml, which was thoroughly mixed with stirring, to prepare a suspension for injection. These preparations for injection were injected subcutaneously, intramuscularly, intraperitoneally or intravaneously in amounts varied from 0.01 ml to 50 ml per day depending on the body weight of the animal.
• Chickens infected artificially with fowl roundworm were employed in groups each consisting of three chickens. Fecal matter testing was conducted before administration of medicine to confirm infection with the worm.
• the quantity of the compound provided for testing was 10 mg and 20 mg per Kg of body weight, which was orally administered each in a gelatin capsule to the chicken.
• the number of worm bodies discharged within 48 hours after administration of medicine was counted, the chicken was killed after 48 hours and the number of worm bodies remaining in the enteron was counted to determine the anthelmintic percentage, wherefrom the antihelmintic effect was judged.
• Chickens artificially infected with fowl roundworm were employed in groups each of two chickens.
• the compound provided for the test was adsorbed on lactose as a solution dissolved in a small amount of ethyl alcohol and added to a chicken feed at levels of 10 ppm and 50 ppm.
• Fecal matter testing was conducted before initiation of the test and on the 7th, 14th and 21st day after initiation of the test. Reduction in worm egg number was examined by calculating E.P.G. (worm eggs per 1 g of fecal matter), and the number of discharged worm bodies and the number of worm bodies remaining in the enteron when the chicken was killed on 21st day were counted to determine the anthelmintic percentage, from which the anthelmintic effect was judged.
• E.P.G. worm eggs per 1 g of fecal matter
• the compound provided for the test was Compound No.Al, and 20 mg/Kg thereof was placed in a gelatin capsule per 1 Kg of body weight, and administered orally to the two dogs. As control, only a gelatin capsule was administered orally to the one dog.
• the compound provided for the test was Compound No.A3, and 10 mg/Kg thereof was placed in a gelatin capsule per 1 Kg of body weight, and administered orally to the two dogs. As control, only a gelatin capsule was administered orally to the one dog.
• mice Six cats were employed. The cats judged to be healthy after destruction of various parasites in their digestive organs during quarantine of 2 weeks or longer were employed as experimental cats. Each experimental cat was infected orally with 5 plerocercoids of Diphyl- lobothrium erinacei collected from beneath the skin of a snake (Rhabdophis) and placed in a gelatin capsule. After infection, fecal matter was tested according to the direct smear method on the lath day and every day thereafter. Infection was judged to be established by detection of worm eggs. The anthelmintic test was performed 15 days after plerocercoid infection.
• the compounds provided for the test were Compound Nos. A3 and A12, and 50 mg thereof per Kg of body weight was placed in a gelatin capsule and administered orally to each of two cats once per day continuously for 5 days. As control, to each of two of the cats, only one gelatin capsule per day was administered orally for 5 days.
• + indicates detection of Diphyllobo- thrium's egg, and - no detection.
• Compound No.A3 was used for the test, and 15 mg thereof was placed in a gelatin capsule per 1 Kg of body weight and administered orally to the two cows. As control, only gelatin capsules were administered orally to the one cow.
• Trichostrongylidae Two sheep infected with Trichostrongylidae (naturally infected sheep) were employed.
• the compound provided for the test was Compound No. Al, 15 mg of which was placed in a gelatin capsule per 1 Kg of body weight and administered orally to one of the sheep. As a control, only gelatin capsules were administered orally to the other sheep.
• the compounds provided for the test were Compound Nos. A3 and A12, 20 mg of each of which was placed in a gelatin capsule per 1 Kg of body weight and administered orally to each of the two pigs. As a control, only gelatin capsules were administered orally to the two pigs.
• the compounds provided for the test were Compound Nos. Al and A10, 20 mg each of which was placed in a gelatin capsule per 1 Kg of body weight, and administered orally to each of the two pigs. As a control, only gelatin capsules were administered orally to the two pigs.
• the compounds provided for tests were Compound Nos. Al, A3 and A12. 20 mg of each was administered by subcutaneous injection per Kg of body weight to each of the two dogs as a suspension in 1% "Tween 80" solution once per day for three days. As control, 3 ml of the 1% "Tween 80" solution was subcutaneously injected into two dogs once per day for three days.
• Twenty-eight (28) rats were employed in fourteen groups each of two rats, each rat being infected with 5 metacercariae of Liver fluke; Fasciola he p atica (F.. hepatica) and confirmed to have worm eggs on the 75th day after infection according to fecal matter testing.
• the compounds provided for the tests were Compound Nos. Al through A13, 50 mg of each of which per Kg of body weight was suspended in 5% gum arabic solution and administered orally once per day continuously for 5.days.
• a liquid preparation was prepared by mixing with stirring 50 g of Compound No. B8, 49 g of ethanol and 1 g of polyvinyl alcohol. This liquid preparation was mixed with stirring into the drinking water for the animal to a concentration of 1% to be suspended in the drinking water, and the resultant suspension was administered to the subject animal.
• Compound No. Bl To 20 g of Compound No. Bl were addded 1 g of sodium carboxymethyl cellulose, 0.2 g of sodium citrate and distilled water for injection to make up a total quantity of 100 ml, and the mixture was thoroughly mixed with stirring to prepare a suspension for injection. These preparations for injection were injected subcutaneously, intramuscularly, intraperitoneally or intravaneously in amounts varied from 0.01 ml to 50 ml per day depending on the body weight of the animal.
• Test Example A2 The same as that in Test Example A2, except that the compound provided for the test was added to a chicken feed at levels of 20 ppm and 50 ppm.
• Test Example A4 The same as that in Test Example A4, but the compound provided for the test was Compound No.B8, and 20 mg/Kg thereof was placed in a gelatin capsule per 1 Kg of body weight and administered orally to the two dogs. As control, only gelatin capsules were administered orally to the one dog.
• + indicates detection of Diphyllobo- thrium's egg, and - no detection.
• Test Example A6 The same as that in Test Example A6, but the compound provided for the test was Compound No. Bl, and 20 mg thereof was placed in a gelatin capsule per 1 Kg of body weight and administered orally to the two cows. As control, only gelatin capsules were administered orally to the one cow.
• Test Example A8 The same as that in Test Example A8, except that the compounds provided for the test were Compound Nos. Bl and B20.
• Test Example A9 The same as that in Test Example A9, but the compounds provided for the test were Compound Nos. B5 and B19. 50 mg of each compound was placed in a gelatin capsule per 1 Kg of body weight and administered orally to each of the two pigs. As control, only gelatin capsules were administered orally to two pigs.
• Test Example A10 The same as that in Test Example A10, but the compounds provided for tests were Compound Nos. Bl, B8, and B9. 30 mg of each compound was administered by subcutaneous injection per Kg of body weight to each of the two dogs as a suspension in 1% "Tween 80" solution once per day for three days. As control, 3 ml of the 1% "Tween 80" solution was subcutaneously injected into two dogs once per day for three days.
• the compounds provided for the tests were Compound Nos. Bl, B8 and B19.
• a liquid preparation was prepared by mixing with stirring 50 g of Compound No.C2, 49 g of ethanol and 1 g of polyvinyl alcohol. This liquid preparation was mixed with stirring into the drinking water for an animal to a concentration of 1% to be suspended in the drinking water, and the resultant suspension was administered to the subject animal.
• Test Example Al The same as that in Test Example Al except that the compound provided for testing was in quantities of 30 mg and 50 mg per Kg of body weight, which were orally administered to the chickens in gelatin capsules.
• Test Example A2 The same as that in Test Example A2, except that the compound provided for the test was added to chicken feed at levels of 25 ppm and 50 ppm.
• Test Example A4 The same as that in Test Example A4, but the compound provided for the test was Compound No. C10, 30 mg/Kg of which was placed in a gelatin capsule per 1 Kg of body weight and administered orally to the two dogs. As control, only gelatin capsules were administered orally to the one dog.
• Test Example A5 The same as in Test Example A5, but the compounds provided for the test were Compound Nos. C2 and C7. 50 mg of each of these compounds per Kg of body weight was placed in a gelatin capsule and administered orally to each of two cats once per day continuously for 5 days. As control, to the two of the cats, was administered orally only one gelatin capsule per day for 5 days.
• Test Example A6 The same as that in Test Example A6, but the compound provided for the test was Compound No. Cl, 20 mg of which was placed in a gelatin capsule per 1 Kg of body weight and administered orally to the two cows. As control, only gelatin capsules were administered orally to the one cow.
• Test Example A8 The same as that in Test Example A8, except that the compounds provided for the test were Compound Nos. C2 and C6.
• Test Example A10 The same as that in Test Example A10, but the compounds provided for tests were Compound Nos. C2, Cl and C9. 30 mg of each compound was administered by subcutaneous injection per Kg of body weight to each of two dogs as a suspension in 1% "Tween 80" solution once per day for three days. As control, 3 ml of the 1% "Tween 80" solution was subcutaneously injected to two dogs once per day for three days.
• the compounds provided for the tests were Compound Nos. C2 and C6.
• a liquid preparation was prepared by adding 10 g of distilled water to 10 g of Compound No. Dl, which step was followed by mixing with stirring. This liquid preparation was added into the drinking water for the animal to a concentration of 5%, which step was followed by mixing with stirring, to be dissolved in the drinking water, and the resultant solution was administered to the subject animal.
• Compound No. D9 To 20 g of Compound No. D9 were added 1 g of sodium carboxymethyl cellulose, 0.2 g of sodium citrate and distilled water for injection to make up a total quantity of 100 ml, and the mixture was thoroughly mixed with stirring to prepare a suspension for injection. These preparations for injection were injected subcutaneously, intramuscularly, intraperitoneally or intravaneously in amounts varied from 0.01 ml to 50 ml per day depending on the body weight of the animal.
• Test Example Al The same as that in Test Example Al, except that the compounds provided for testing were used in quantities of 15 mg and 30 mg per Kg of body weight, which were orally administered each in a gelatin capsule to the chicken.
• Test Example A10 The same as that in Test Example A10, but the compounds provided for tests were Compound Nos. D10, D13 and D16. 20 mg of each compound was administered by subcutaneous injection per kg of body weight once per day for three days to each of two dogs. These compounds were administered as a suspension in 1% "Tween 80" in the case of Compound No.Dl3 and as solutions dissolved in distilled water for injection in the case of Compounds Nos. D10 and D16, respectively. As control, 3 ml of the 1% "Tween 80" solution was subcutaneously injected into two dogs once per day for three days.
• the compound of Compound No. El (20g) and 78 g of calcium carbonate were milled and mixed well in a ball mill. 2 g of magnesium stearate was further added thereto, and the mixture was further milled and mixed. The mixture was fed into a tabletting machine to produce tablets each of 1 g (200 mg as effective ingredient). This tablet was administered orally in various doses from 0.2 to 250 g per day depending on the body weight of the animal.
• a liquid preparation was prepared by mixing under stirring 50 g of Compound No. E3, 49 g of ethanol and 1 g of polyvinyl alcohol. This liquid preparation was mixed with stirring into the drinking water for the animal to a concentration of 1% to be suspended in the drinking water, and the resultant suspension was administered to the subject animal.
• Compound No. E6 To 20 g of Compound No. E6 were added 1 g of sodium carboxymethyl cellulose, 0.2 g of sodium citrate and distilled water for injection to make up a total quantity of 100 ml, and the mixture was thoroughly mixed with stirring, to prepare a suspension for injection. These preparations for injection were injected subcutaneously, intramuscularly, intraperitoneally or intravaneously in amounts varied from 0.01 ml to 50 ml per day depending on the body weight of the animal.
• the compound provided for testing was orally administered in a quantity of 40 mg per Kg of body weight to each chicken in a gelatin capsule.
• the number of worm bodies discharged within 24 hours after administration of the medicine was counted.
• the chicken was killed, and the number of worm bodies remaining in the enteron was counted to determine the anthelmintic percentage, wherefrom the anthelmintic effect was judged.
• the compound provided for the test was dissolved in a small amount of ethyl alcohol and adsorbed on defatted rice bran and added to chicken feed at levels of 2 50 ppm and 1,000 ppm. As control, a feed containing no such compound was employed.
• Fecal matter testing was conducted before initiation of the test and on the 5th day after initiation of the test.
• the reduction in worm egg count was examined by calculating the E.P.G. (worm egg number in 1 g of fecal matter).
• the number of discharged worm bodies and the number of worm bodies remaining in the enteron when the chicken was killed on 5th day were counted to determined the anthelmintic percentage, from which the anthelmintic effect was judged.

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• Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
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• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

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• 1983
  • 1983-09-21 EP EP83109398A patent/EP0103895A3/de not_active Withdrawn
  • 1983-09-21 DK DK431083A patent/DK431083A/da not_active Application Discontinuation
  • 1983-09-21 AU AU19335/83A patent/AU1933583A/en not_active Abandoned
  • 1983-09-22 FR FR8315074A patent/FR2546884A1/fr not_active Withdrawn

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